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Flash droughts develop and intensify rapidly under the influence of abnormally high temperatures, wind speed, radiation and declining of the normal precipitation rate. The changing of Potential evapotranspiration (PET) and soil moisture is considered as key early warning and development of flash drought indicators.In this study, we first analyse spatio-temporal trends of the PET at monthly, seasonal, and annual temporal scales in Sicily. PET is estimated by the Penman-Monteith method based on a network of 46 meteorological stations, at daily metrological data. The Mann Kendall test and Sen’s slope analysis are applied to identify the significance of PET trends in the region. Result showed increasing trends for most of the months and the region. For instance, August had the highest increasing PET monthly trend, with a maximum of 1.73 mm per year and the highest increasing annual trend was 10.68 mm per year. Findings of this analysis provide preliminary insights on how climate change can influence PET.Then, we carry out a preliminary investigation of flash droughts based on a joint analysis of potential evapotranspiration and soil moisture. In particular, based both on the network of meteorological stations and reanalysis data of soil moisture at hourly resolution, daily potential evapotranspiration (PET) and soil estimations at different soil depths are analysed with the method of runs. Considering different thresholds, the runs of PET and soil moisture are compared to characterize flash drought periods and to understand the relation between the two variables. Results indicate a significant link between the variables, and thus a potential for developing flash drought monitoring tools. Keywords: Flash drought, Potential evapotranspiration (PET), Spatiotemporal, Trend, Sicily

A drought is notoriously considered as one of the most complex natural phenomena, which, more than other natural hazards, remains difficult to quantitatively model with an inferential approach due to the scarcity of events in the historical record. One possible solution to overcome this problem relies on the use of proxy climatic data to extend the instrumental record. Additionally, since droughts are rarer than floods, techniques which optimally use available information, such as the metastatistical framework, can be extremely beneficial.This work exploits a publicly available tree-ring based Old World Drought Atlas (OWDA; Cook et al., 2015), a reconstruction of the summer self-calibrating Palmer Drought Severity Index, to model the stochastic nature of the drought characteristics. Drought events are defined in terms of the deficit volume using the statistical “theory of runs”. We then explore the potential of the Metastatistical Extreme Value Distribution (MEVD) to estimate the probability of occurrence of drought events and compare its performance with that obtained by the use of traditional approaches. A cross-validation scheme, dividing the available data into independent calibration and test sub-sample, is used to quantify the estimation uncertainty associated with different sample sizes and estimation methods.The analysis of extreme droughts in two case studies in Italy suggests that the MEVD-based formulations are more robust and flexible approaches with respect to traditional ones. The comparative analysis of the predictive estimation uncertainty is site-specific, but MEVD estimates outperform, in terms of bias and uncertainty, traditional GEV estimates., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

A key component for Landslide early warning systems (LEWS) is constituted by thresholds that provide the conditions under which landslide events can be potentially triggered. Traditionally, thresholds based on rainfall characteristics have been proposed, but recently, the hydro-meteorological approach, combining rainfall with soil moisture or catchment storage information, is increasingly gaining attention. Usually, the hydro-meteorological thresholds proposed in the literature rely on soil moisture information relating to a single layer (i.e., depth or depth range). Nevertheless, multi-layered soil moisture information can be readily provided by in-situ observations, reanalysis projects, or hydrological models. Approaches based on this multi-layered information are lacking, probably because simpler thresholds, e.g., two-dimensional, are preferred and better understood by decision makers. This study, thus, proposes a methodology, based on principal component analysis (PCA), to derive two-dimensional hydro-meteorological thresholds that use multi-layer soil moisture information. Furthermore, a piece-wise linear equation is also suggested as threshold’s shape, which can be more flexible than the traditional power-law or bi-linear thresholds. Overall, results for Sicily Island (Italy), obtained using reanalysis soil moisture data at four different depths, corroborate the advantages of the hydro-meteorological approach with respect to the traditional rainfall thresholds. Specifically, a True Skill Statistic Index (TSS) equal to 0.5 is obtained for the traditional precipitation intensity-duration threshold, while a significantly higher one is obtained for the proposed hydro-meteorological thresholds using multi-layer information condensed in one variable by PCA (TSS = 0.71). Furthermore, comparing single- vs. multi-layer threshold performances provides insights on whether shallow or deep soil depth hydrological processes are more or less influent on landslide triggering. In this regard, for the analyzed study area, the multi-layer approach provides performances in terms of TSS are similar to those obtained with single-layer soil moisture at the upper depths, 0-7 cm and 7-28 cm, pointing out that landslide occurrences in Sicily are mostly driven by surface soil moisture.

As a consequence of climate change and rapid urbanization, floods have increased both in terms of intensity and frequency, impacting especially the less developed countries of the World, and particularly sub-Saharan Africa. In such contexts, reliable flood risk assessments are of primary importance to support local authorities and stakeholders in emergency management and planning, and in the definition of effective risk mitigation measures. Still, their implementation is often hampered by lack of suitable data and resources. The present study has the main objectives of presenting challenges and identified solutions of performing flood hazard and risk analysis for the Megaruma and Muaguide rivers in Cabo Delgado, the northern province of Mozambique and also the poorest one. The downstream paths of the rivers cross the districts of Mecufi and Metuge, rural areas covered by fields cultivated by inhabitants who live on subsistence agriculture. During the wet season, some of the villages are completely isolated, with no access to adequate health services due to the floods that periodically affect the local population and their activities. As for many developing countries, data scarcity was the first limiting factor for quantitative analysis; therefore, much effort was primarily invested into data research. The hydrologic and hydraulic modelling to determine the flood hazard in the areas rely on free or at least cheap, global data (rainfall, terrain elevation and soil cover), meeting the second requirement of low available budget. On the contrary, an intensive field survey was required to collect data on the vulnerability of exposed assets at the base of damage assessment. Particular attention was also paid in the choice of free softwares and modelling tools. The resulting approach and methods can be easily exported to similar contexts, enabling robust flood risk analyses in the support of sustainable development.

Water resources management is becoming increasingly challenging under current climate change. Water utilities need to assess planning adaptation strategies aimed at sustainable water resource exploitation. In this study, we estimate the potential impacts of climate change on hydrological variables and future spring discharge availability. Specifically, we exploit an empirical regressive model based on the statistical relationship between Standardized Precipitation-Evapotranspiration Index (SPEI) and minimum annual spring discharge, in combination with Regional Climate Models (RCMs) provided by the EURO-CORDEX initiative. In this regard, two Representative Concentration Pathways (RCPs) are considered, RCP4.5 (intermediate emissions scenario) and RCP8.5 (high emissions scenario), as well as two future time horizons, namely the near future 2021-2050 and the far future 2041-2070. Then, after bias correction of the so estimated minimum spring discharge values, the curves relating spring discharge and reliability in satisfying water demand are assessed. We carried out our investigation for karst aquifers located in the Italian Apennines, which are used for the water supply system of the city of Rome (Italy) and the surrounding areas, managed by ACEA Ato2, serving over 4 million users. Overall, the results indicate a general decrease in the demand that can be satisfied with high reliability, pointing out significant potential impacts of climate change on water availability on both near and far future. The proposed methodology could be a useful tool for water managers, since it provides a support for planning adaptation measures aimed at minimizing future socio-economic impacts of climate change.

Objective Mild to moderate hypertriglyceridemia is a condition often associated with obesity and diabetes, with as yet incomplete knowledge of underlying genetic architecture. The 22q11.2 microdeletion is associated with multimorbidity, including increased risk of obesity and diabetes. In this study, we sought to investigate whether the 22q11.2 microdeletion was associated with mild to moderate hypertriglyceridemia (1.7–10 mmol/L). Design This was a cohort study comparing 6793 population-based adults and 267 with a 22q11.2 microdeletion aged 17–69 years, excluding those with diabetes or on statins. Methods We used binomial logistic regression modeling to identify predictors of hypertriglyceridemia, accounting for the 22q11.2 microdeletion, male sex, BMI, ethnicity, age, and antipsychotic medications. Results The 22q11.2 microdeletion was a significant independent predictor of mild to moderate hypertriglyceridemia (odds ratio (OR): 2.35, 95% CI: 1.70–3.26). All other factors examined were also significant predictors (OR: 1.23–2.10), except for antipsychotic medication use. Within the 22q11.2 microdeletion subgroup, only male sex (OR: 3.10, 95% CI: 1.77–5.44) and BMI (OR: 1.63, 95% CI: 1.14–1.98) were significant predictors of hypertriglyceridemia, evident at mean age 31.2 years. Conclusions The 22q11.2 microdeletion is associated with hypertriglyceridemia even when accounting for other known risk factors for elevated triglycerides. This effect is seen in young adulthood (76.6% were

BackgroundCone-beam computed tomography (CBCT) imaging of the brain can be performed in the angiography suite to support various neurovascular procedures. Relying on CBCT brain imaging solely, however, still lacks full diagnostic confidence due to the inferior image quality compared with CT and various imaging artifacts that persist even with modern CBCT.ObjectiveTo perform a detailed evaluation of image artifact improvement using a new CBCT protocol which implements a novel dual-axis ‘butterfly’ trajectory.MethodsOur study included 94 scans from 47 patients who received CBCT imaging for assessment of either ischemia or hemorrhage during a neurovascular procedure. Both a traditional uni-axis ‘circular’ and novel dual-axis ‘butterfly’ protocol were performed on each patient (same-patient control). Each brain scan was divided into six regions and scored out of 3 based on six artifacts originating from various physics-based and patient-based sources.ResultsThe dual-axis trajectory produces CBCT images with significantly fewer image artifacts than the traditional circular scan (whole brain average artifact score, AS: 0.20 vs 0.33), with the greatest improvement in bone beam hardening (AS: 0.13 vs 0.78) and cone-beam artifacts (AS: 0.04 vs 0.55).ConclusionsRecent developments in CBCT imaging protocols have significantly improved image artifacts, which has improved diagnostic confidence for stroke and supports a direct-to-angiography suite transfer approach for patients with acute ischemic stroke.

The Cell Model Network-UK group author list

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Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.Significance:We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.This article is highlighted in the In This Issue feature, p. 1861

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PDF file - 635K, Supplementary Figure S1. Genotypes included in the combinatorial genetic matrix. PTEN or RB1 were silenced by shRNA in isogenic KI cells.

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XLSX file - 144K, Supplementary table S1. List of compounds employed in the present work. Supplementary Table S2. List of t-tests p values comparing the responses of the different mutant cell lines to a given drug concentration with the response of the WT Scramble control cells. Supplementary Table S3. List of the drugs included in the library and tested on HME-1 cell lines.

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A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair—or boost—the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug–genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios. We screened a library of 43 compounds in human hTERT-HME1 epithelial cells in which PTEN or RB1 were silenced in combination with the targeted knockin of cancer-associated mutations in EGFR, KRAS, BRAF, or PIK3CA oncogenes. Statistical analysis and clustering algorithms were applied to display similar drug response profiles and mutation-specific patterns of activity. From the screen, we discovered that proteasome inhibitors show selectivity toward BRAF V600E–mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of BRAF-mutant cells by proteasome inhibitors was corroborated in a second BRAF V600E isogenic model, as well as in a panel of colorectal cancer cell lines by the use of the proteasome inhibitor carfilzomib. Notably, carfilzomib also showed striking in vivo activity in a BRAF-mutant human colorectal cancer xenograft model. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in BRAF V600E–mutant colorectal tumors. Mol Cancer Ther; 12(12); 2950–61. ©2013 AACR.

Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer.Significance:The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079

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Purpose:Patient-derived xenograft (PDX) models accurately recapitulate the tumor of origin in terms of histopathology, genomic landscape, and therapeutic response, but some limitations due to costs associated with their maintenance and restricted amenability for large-scale screenings still exist. To overcome these issues, we established a platform of 2D cell lines (xeno-cell lines, XL), derived from PDXs of colorectal cancer with matched patient germline gDNA available.Experimental Design:Whole-exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the WRN helicase gene was assessed in MSS, MSI-H, and MSI-like XLs using a reverse genetics functional approach.Results:XLs recapitulated the entire spectrum of colorectal cancer transcriptional subtypes. Exome and RNA-seq analyses delineated several molecular biomarkers of response and resistance to EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XLs were confirmed in vivo in the matched PDXs. MSI-H models were dependent upon WRN gene expression, while loss of WRN did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to WRN depletion.Conclusions:The XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.

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Supplementary Figure from Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer

Supplementary Table from Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer

The file lists Supplementary Materials and Methods and relative References.

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Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1. These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504–15. ©2016 AACR.

Supplementary Tables S1-S3 - List of drug concentrations to generate resistant cell lines (S1); Drug concentrations applied in the screening depicted in Figure 6 (S2); Primers for gene amplification and sequencing (S3). Supplementary Figure S1. Synergistic activity of targeted therapy combinations in BRAF mutant colorectal cancer cells. Supplementary Figure S2. Amplification of mutant BRAF V600E confers resistance to combined EGFR and MEK targeting in colorectal cancer cells. Supplemental Figure S3. Cytotoxicity induced by ERK inhibition in VACO432 resistant to BRAF combination therapies.

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Purpose:Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored.Experimental Design:We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs.Results:We found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines.Conclusions:In conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.

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Purpose:Defects in the homologous recombination (HR) repair pathway are of clinical interest due to sensitivity of HR-deficient cells to PARP inhibitors. We were interested in defining PARP vulnerability in patients with metastatic colorectal cancer (mCRC) carrying KRAS and BRAF mutations who display poor prognosis, have limited therapeutic options, and represent an unmet clinical need.Experimental Design:We tested colorectal cancer cell lines, patient-derived organoids (PDO), and patient-derived xenografts (PDX) enriched for KRAS and BRAF mutations for sensitivity to the PARP inhibitor olaparib, and the chemotherapeutic agents oxaliplatin and 5-fluorouracil (5-FU). Genomic profiles and DNA repair proficiency of colorectal cancer models were compared with pharmacologic response.Results:Thirteen of 99 (around 13%) colorectal cancer cell lines were highly sensitive to clinically active concentrations of olaparib and displayed functional deficiency in HR. Response to PARP blockade was positively correlated with sensitivity to oxaliplatin in colorectal cancer cell lines as well as patient-derived organoids. Treatment of PDXs with olaparib impaired tumor growth and maintenance therapy with PARP blockade after initial oxaliplatin response delayed disease progression in mice.Conclusions:These results indicate that a colorectal cancer subset characterized by poor prognosis and limited therapeutic options is vulnerable to PARP inhibition and suggest that PDO-based drug-screening assays can be used to identify patients with colorectal cancer likely to benefit from olaparib. As patients with mCRC almost invariably receive therapies based on oxaliplatin, “maintenance” treatment with PARP inhibitors warrants further clinical investigation.

Computational fluid dynamics (CFD) of cerebral venous flows has become popular owing to the possibility of using local hemodynamics and hemoacoustics to help diagnose and plan treatments for venous diseases of the brain. Lumen geometries in low-pressure cerebral veins are different from those in cerebral arteries, often exhibiting fenestrations and flattened or triangular cross section, in addition to constrictions and expansions. These can challenge conventional size-based volume meshing strategies, and the ability to resolve nonlaminar flows. Here we present a novel strategy leveraging estimation of length scales that could be present if flow were to become transitional or turbulent. Starting from the lumen geometry and flow rate boundary conditions, centerlines are used to determine local hydraulic diameters and cross-sectional mean velocities, from which flow length scales are approximated using conventional definitions of local Kolmogorov and Taylor microscales. By inspection of these scales, a user specifies minimum and maximum mesh edge lengths, which are then distributed along the model in proportion to the approximated local Taylor length scales. We demonstrate in three representative cases that this strategy avoids some of the pitfalls of conventional size-based strategies. An exemplary CFD mesh-refinement study shows convergence of high-frequency flow instabilities even starting from relatively coarse edge lengths near the lower bounds of the approximated Taylor length scales. Rational consideration of the length scales in a possibly nonlaminar flow may thus provide a useful and replicable baseline for denovo meshing of complicated or unfamiliar venous lumen geometries.